Gene silencing and antifibril therapy could stop disease progression and eliminate amyloid deposits in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), according to a study recently published in European Heart Journal Supplements.
“ATTR amyloidosis was previously treated only through liver transplantation, whereas recent advancements have introduced a variety of pharmacological therapies targeting different stages of the amyloidogenic process, from TTR stabilization to gene editing,” study authors said.
What is ATTR-CM?
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a rare progressive disease of the heart muscle that leads to congestive heart failure. It occurs when the transthyretin protein produced by the liver is unstable. Symptoms include fatigue; shortness of breath; irregular heart rate or palpitations; swelling of the legs, ankles and stomach; brain fog; wheezing; and dizziness. It often goes underdiagnosed because of a lack of awareness and knowledge of the disease. There is currently no cure for ATTR-CM.
Tamidis is the only approved disease-modifying therapy for patients with ATTR-CM. The drug has proven to increase patient quality of life and functional capacity. Other experimental drugs currently being investigated in clinical trials could offer further benefits to patients with the disease.
Read more about ATTR-CM therapies
For example, acoramidis binds to TTR with greater selectivity than tafamidis, making it in theory more efficient in preventing amyloid deposition.
A recent Phase 3 clinical trial demonstrated that ceramides reduced mortality, hospitalization frequency and cardiac biomarker levels.
Unlike TTR stabilizers such as acoramidis and tafamidis, TTR stabilizers directly reduce the production of TTR by the liver. Patisiran, which has already received approval for treating ATTR polyneuropathy, can reduce amyloid deposition by around 80% and significantly improved cardiac biomarker levels. Vutrisiran, another TTR silencer, offers similar benefits but requires less frequent dosing than patisiran.
More recently, gene editing with CRISPR-Cas9 technology can permanently modify the TTR gene in liver cells and prevent amyloid deposition with a single dose. According to one study, a single dose of nexiguran ziclumeran can reduce TTR levels by almost 100% with no severe adverse effects.
Antibody therapy against TTR appears to be a promising alternative for eliminating amyloid deposits that accumulated in tissue prior to initiating TTR stabilizing or silencing therapy. Several antibodies are currently being evaluated in clinical trials and have shown promising results so far.
“Ongoing research and clinical trials will be crucial in refining the best therapeutic approaches for CA, integrating both disease-modifying therapies and heart failure treatments,” the authors said. ”Ultimately, improving the prognosis for individuals affected by this life-threatening condition.”
Sign up here to get the latest news, perspectives and information about ATTR-CM sent directly to your inbox. Registration is free and takes only a minute.
